Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age

Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Stem Cell Research, and Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 11/2011; 108(50):20012-7. DOI: 10.1073/pnas.1116110108
Source: PubMed

ABSTRACT In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.

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    • "Fasting Inhibits IGF-1/PKA to Promote Regeneration myeloid-biased, and balanced-HSCs ratio (Figures 2F, S2D, and S2E). Whereas most HSCs from young mice are balanced in lymphopoiesis and myelopoiesis, the majority of HSCs from elderly mice are myeloid biased (Beerman et al., 2010; Challen et al., 2010; Cho et al., 2008; Dykstra et al., 2007; Morita et al., 2010; Muller-Sieburg et al., 2004; Pang et al., 2011). We therefore investigated if PF cycles can correct this bias in aged mice. "
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    ABSTRACT: Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration.
    Cell Stem Cell 06/2014; 14(6):810-823. DOI:10.1016/j.stem.2014.04.014 · 22.15 Impact Factor
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    • "Loss of Wnt and T-cell potential in aged human HSCs, M. L. M. Khoo et al. capability for specification to the myeloid lineage, but insufficient levels for T-lymphocyte differentiation. In addition, this intrinsic defect in Wnt signaling of aged human HSCs may contribute to the reported myeloidbiased skewing of differentiation potential that is associated with aging of the hematopoietic system (Pang et al., 2011). Interaction or cross talk between the Notch and Wnt signaling pathways has been reported with increasing frequency (Munoz Descalzo & Martinez Arias, 2012). "
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    ABSTRACT: Functional decline of the hematopoietic system occurs during aging and contributes to clinical consequences, including reduced competence of adaptive immunity and increased incidence of myeloid diseases. This has been linked to aging of the hematopoietic stem cell (HSC) compartment and has implications for clinical hematopoietic cell transplantation as prolonged periods of T-cell deficiency follow transplantation of adult mobilized peripheral blood (PB), the primary transplant source. Here, we examined the gene expression profiles of young and aged HSCs from human cord blood and adult mobilized PB, respectively, and found that Wnt signaling genes are differentially expressed between young and aged human HSCs, with less activation of Wnt signaling in aged HSCs. Utilizing the OP9-DL1 in vitro co-culture system to promote T-cell development under stable Notch signaling conditions, we found that Wnt signaling activity is important for T-lineage differentiation. Examination of Wnt signaling components and target gene activation in young and aged human HSCs during T-lineage differentiation revealed an association between reduced Wnt signal transduction, increasing age, and impaired or delayed T-cell differentiation. This defect in Wnt signal activation of aged HSCs appeared to occur in the early T-progenitor cell subset derived during in vitro T-lineage differentiation. Our results reveal that reduced Wnt signaling activity may play a role in the age-related intrinsic defects of aged HSCs and early hematopoietic progenitors and suggest that manipulation of this pathway could contribute to the end goal of improving T-cell generation and immune reconstitution following clinical transplantation.
    Aging cell 05/2014; 13(4). DOI:10.1111/acel.12229 · 5.94 Impact Factor
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    • "Further, aged HSCs show a differentiation preference toward myeloid lineages at the expense of lymphoid differentiation (Morrison et al., 1996; Sudo et al., 2000; Liang et al., 2005; Rossi et al., 2005; Chambers et al., 2007). In humans, aged HSCs also show increased frequency and a bias toward myeloid potential (Pang et al., 2011). "
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    ABSTRACT: The age-dependent decline in the self-renewal capacity of stem cells plays a critical role in aging, but the precise mechanisms underlying this decline are not well understood. By limiting proliferative capacity, senescence is thought to play an important role in age-dependent decline of stem cell self-renewal, although direct evidence supporting this hypothesis is largely lacking. We have previously identified the E3 ubiquitin ligase Smurf2 as a critical regulator of senescence. In this study, we found that mice deficient in Smurf2 had an expanded hematopoietic stem cell (HSC) compartment in bone marrow under normal homeostatic conditions, and this expansion was associated with enhanced proliferation and reduced quiescence of HSCs. Surprisingly, increased cycling and reduced quiescence of HSCs in Smurf2-deficient mice did not lead to premature exhaustion of stem cells. Instead, HSCs in aged Smurf2-deficient mice had a significantly better repopulating capacity than aged wild-type HSCs, suggesting that decline in HSC function with age is Smurf2 dependent. Furthermore, Smurf2-deficient HSCs exhibited elevated long-term self-renewal capacity and diminished exhaustion in serial transplantation. As we found that the expression of Smurf2 was increased with age and in response to regenerative stress during serial transplantation, our findings suggest that Smurf2 plays an important role in regulating HSC self-renewal and aging.
    Aging cell 02/2014; DOI:10.1111/acel.12195 · 5.94 Impact Factor
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